ABSTRACT The main goal is to identify protective genetic variants from a group of high-risk PSEN1-G206A mutation carriers. If successful, we may be able to learn how these protective variants may delay the age at onset (AAO) of dementia or age-related memory decline. In 2001, we identified a founder mutation in PSEN1 (G206A) in family members from eight Caribbean Hispanic families with origins in Puerto Rico. The average age at onset with this mutation was unusually late (mean: 55.6 years) and was remarkably variable within as well as across families, ranging from 22-77 years. In this group of Puerto Rican families with multiple affected family members, this mutation was as prevalent as APOE ?4, but, unlike APOE ?4 carriers who have a 2- to 3- fold increased risk of AD, most PSEN1 carriers will develop Alzheimer disease (AD) eventually. Our pilot whole exome sequencing (WES) study identified 6 candidate genes that may harbor variants that alter the AAO of AD, and these variants accounted for as much as 15-20 year differences in AAO of AD [2]. We then showed that 3 out of 6 genes had SNPs that were associated with variable AAO in individuals with late onset AD (LOAD), suggesting that these may be generalizable to LOAD, the most common form of AD. This study proposes to integrate whole genome sequencing (WGS) data with genome wide SNP (GWAS) data to identify genetic modifiers of AAO or memory traits by focusing on this set of the G206A carrier families. To date, we have recruited and examined over 75 extended EOAD families that have at least one person who carry the G206A mutation. Most individuals have in-depth phenotype data and GWAS data. Further, we have established collaboration with Dr. Kosik who study a Colombian cohort with a different PSEN1 (E280) mutation which will allow independent confirmation. In addition, we will be able to employ the high dimensional multi- omic data of ROS/MAP from the collaboration with Dr. De Jager?s group. To assess generalizability, we will be able to access independent sets of unrelated Caribbean Hispanics and non-Hispanic Whites to further confirm the allelic association, and then to examine how clinically relevant these variants are in general populations. Lastly, we will use cell based systems to test the role of modifiers in the A? pathway. Taking all the genetic resources together, we will be able to interrogate the genomes of this unique cohort with a founder mutation to identify protective variants and genes. We will: (1) conduct a WGS study to identify novel variants; (2) characterize the relations between novel modifier variants and AAO or memory through examination of transcriptomic and external genomic data of EOAD and LOAD; and (3) investigate the mechanisms of action of modifiers of PSEN1 using human fibroblast and iPSC-derived neuronal cultures. If successful, it may be possible to identify a potential therapeutic target(s) that might delay or prevent AD or maintain healthy cognition.